Translation of the abstract (English)

The Parkinson's disease, named after his discoverer, the London doctor Dr. James Parkinson, is clinical characterized by the motor cardinal symptoms rigor, tremor, akinesia and postural instability. A degeneration of the dopaminergic neurons of the substantia nigra pars compacta (SNc) of the midbrain which leads to a deprivation of dopamine in the striatum and is the cause for the ...

Translation of the abstract (English)

The Parkinson's disease, named after his discoverer, the London doctor Dr. James Parkinson, is clinical characterized by the motor cardinal symptoms rigor, tremor, akinesia and postural instability. A degeneration of the dopaminergic neurons of the substantia nigra pars compacta (SNc) of the midbrain which leads to a deprivation of dopamine in the striatum and is the cause for the neuropathological motor symptoms.

The idiopathic Parkinson's syndrome (IPS) is the most frequent form of the Parkinson's disease and belongs to the most frequent illnesses of the central nervous system and is after Morbus Alzheimer the second most frequent neurodegenerative illness (McDonald et al., in 2003). The manifestation age lies between 50 and 79 years, with a middle age of illness beginning between 58 and 62 years. Men and women are equally affected (Müller, in 2002).

The cause of the IPS is widely unsettled. Different risk factors could be defined. Rising age is one of the biggest risk factor in the development of IPS. With increasing patient's age more and more neurons perish in the CNS, therefore also in the SN. Nevertheless, besides, it concerns not exclusively dopaminergic neurons of the SNc. McGeer could show that with rising age the tyrosine hydroxylase activity is decreased as a limiting factor by the change by tyrosine to dopamine by which dopamine is available in lower concentration (McGeer, in 1971).

In spite of introduction of the therapy with L-dopa and with the linked rising life expectancy of the affected patients the survival time is significantly decreased by patients with IPS compared to people of the same age (D'Amelio et al., in 2006).

In the treatment of motoric deficits within idiopathic Parkinson’s syndrome (IPS) different dopamine agonists (DA) are commonly used in daily practice. DA can be subdivided chemically in two categories: ergotalkaloids including pergolide, lisuride, cabergoline, bromocriptine and α-dihydroergocryptine and the non-ergotalkaloids comprising the active substance group apomorphine, pramipexole, ropinirole, rotigotine and piribedil.

Currently there are used different DA in the therapy of the IPS. Up to now at least 5 receptor subtypes of dopamine receptors could be described (D1-5). The pharmacologic division is divided in two main families according to the effective structure: type D1 (D1, D5) and D2 (D2-D4). DA work mainly on D2 receptors. The connections between receptor subtype, DA and clinical use are discussed controversially. On the other hand DA also work on other receptors.

The so called DA work as highly potent agonists on the serotonine receptor subtype 5-HT2B. Among the rest, this receptor subtype is expressed in high quantity on heart flaps. An activation induces the mitogenesis with consecutive myofibroblast proliferation and gives rise to fibrosis of the heart flaps with a remaining sound flap structure (Fitzgerald et al., in 2000, Rothman et al., in 2000). The migraine remedy ergotamine and methylergonovine, as well as the anorectic remedies fenfluramine and dexfenfluramine are part of a drug group which can damage the heart flaps according the described mechanism (Fitzgerald et al., in 2000). In addition, the fibrotic changes are identical to those which can be observed in patients with a serotonine producing carcinoid tumour (Møller et al., in 2003).

Different studies could have proved an emerging fibrosis of heart valves during pergolide treatment of IPS patients and have induced a controversial discussion regarding the therapeutic security of dopamine agonists towards heart alternations. Single case reports of heart valve alternations and heart valve insufficiency gave rise to the assumption of a pathophysiological relation between heart valve fibrosis and ergot dopamine agonists. The present study deals with the question of an existing relation between treatment of ergot dopamine agonists and valvulopathy.

Therefore in this present retrospective study we performed transthoracic echocardiography on 66 patients with diagnosed IPS according to the criteria of the “American Society of Echocardiography”. Performance was analyzed regarding the clinical parameters of age, course of disease and medical treatment. All transthoracic echocardiographies have been performed with a Siemens Sequoia device by a medical specialist in cardiology.

The frequency of restrictive valvulopathy has been analyzed in 66 patients with diagnosed IPS. Patients got treatment with pergolide (n=23), cabergoline (n=22), pramipexole (n=4), ropinirole (n=6) or L-dopa (n=11). In the pergolide group five patients (22%), in the cabergoline group four patients (18%) were diagnosed with restrictive valvulopathy. No evidence of restrictive valvulopathy was found in the 21 patients treated with L-dopa or other non-ergot dopamine agonists. The difference between cumulative dosage and exposition period of affected and non-affected patients was merely significant in the pergolide group regarding the exposition period. No significance was detected regarding the age of affected and non-affected patients. Heart valve insufficiency was detected more frequently in pergolide and cabergoline group. The mitral valve was affected more frequently in the ergot group than in the non-ergot and L-dopa group. Heart valve insuffiency of second or third degree occurred more frequently in the non-ergot group than in the L-dopa group.

The observation that restrictive valvulopathies occured only in the test group with the ergot dopamine agonists pergolide and cabergoline could be to be explained by the fact that both substances are highly potent agonists of the serotonine receptor subtype 5-HT2B. 5-HT2B receptors are expressed particular on heart flaps and their activation causes a mitogenesis with consecutive myofibroblasts proliferation which can cause pathophysiologically a fibrosis of the heart flaps.

The results are in accord with recent published studies showing an increased risk of restrictive valvulopathy in patients with idiopathic Parkinson's syndrome that are treated with cabergoline or pergolide.